A vast pharmacopeia is available to treat conditions ranging from the annoyance of dry skin to life-threatening diseases. Many of these remedies can be administered orally, either through ingestion or inhalation, or through the skin as a patch or ointment. Others are susceptible to enzymatic degradation by proteases and other chemicals in the gastrointestinal (GI) tract or exhibit poor permeability through the skin or intestinal epithelial cells (enterocytes). Such drugs must be administered through less convenient methods, for example, by injection.
Unless a pharmaceutical is administered continuously, for example, using an intravenous drip, the serum levels of the drug will not be continuous. Serum levels will spike shortly after administration and then tail off in a non-linear fashion. While there may be an optimal serum concentration, a patient will only experience this optimum concentration briefly, as the concentration of the drug decreases from the initial spike. While the average concentration over time may be correct, the actual serum concentration of the drug will practically always be greater or less than optimal.
Another factor that tends to impede a patient's receipt of the proper quantity of a drug is patient compliance. Many patients are unwilling or unable to comply with a physician's instructions describing how often to take a drug. It is inconvenient and confusing to take several drugs at different times during the day and painful to inject protein drugs such as insulin.
The use of controlled-release formulations to provide a consistent dose of a drug to a patient has been an active area of research for decades and has been fueled by the many recent developments in polymer science and the need to deliver more labile pharmaceutical agents such as nucleic acids, proteins, and peptides. Controlled release polymer systems can be designed to provide a drug level in the optimum range over a longer period of time than other drug delivery methods, thus increasing both the efficacy of the drug and patient compliance.
Biodegradable particles have been developed as sustained release vehicles used in the administration of small molecule drugs as well as protein and peptide drugs and nucleic acids (Langer, Science, 249:1527-1533, 1990; Mulligan, Science, 260:926-932, 1993; Eldridge, Mol. Immunol., 28:287-294, 1991; the entire teaching of each of the foregoing references is incorporated herein by reference). The drugs are typically encapsulated in a polymer matrix which is biodegradable and biocompatible. As the polymer is degraded or dissolved and/or as the drug diffuses out of the polymer, the drug is released into the body. Typically, polymers used in preparing these particles are polyesters such as poly(glycolide-co-lactide) (PLGA), polyglycolic acid, poly-β-hydroxybutyrate, and polyacrylic acid ester. These particles have the additional advantage of protecting the drug from degradation by the body.
Still, it is desirable to have controlled-release system that can be used for oral administration of substances that are not normally stable in the gastrointestinal tract or that are difficult to transport across the intestinal mucosa into the bloodstream. Oral delivery is expected to result in enhanced patient compliance, resulting in improved clinical outcomes, largely due to ease of drug administration as compared to subcutaneous or intravenous injection. An appropriate delivery system that can 1) encapsulate protein and other labile drugs, 2) protect the drugs while in transit through the gastrointestinal (GI) tract, 3) efficiently transport the drugs across the intestinal mucosa, and 4) efficiently release the drugs in the systemic circulation may result in high bioavailability of protein drugs after oral administration. Even for drugs that are stable in the GI tract, a delivery system that can transport them across the intestinal mucosa and release them directly into the bloodstream can enhance bioavailability.